Chapter 98: Liver Ischemia-Reperfusion Injury

CLINICAL IMPACT

• Ischemia-reperfusion (I/R) injury is a technically unavoidable complication of transplantation.

• It has been implicated as an important etiologic factor in the pathogenesis of acute and chronic graft failure in up to 30% of liver transplants.¹

• The use of extended-criteria organs amplifies the problem with liver I/R, as many of these organs are more susceptible to the consequences of I/R, including steatotic donor livers and livers with prolonged ischemic time.²

PATHOPHYSIOLOGY

• The cessation of blood flow has multiple effects on an organ. The primary consequences are decreased oxygen delivery (hypoxia) and decreased clearance of toxic metabolites.

• Hypoxia is the major culprit in ischemic liver injury.

  • A study of isolated rat livers suggests that the extent of liver injury occurring due to ischemia can be replicated by the perfusion of hypoxic blood.³

  • Hypoxia results in the depletion of adenosine triphosphate (ATP), which is required to sustain multiple cellular processes, including:

    • Maintenance of Na⁺/K⁺ pumps

    • Protein synthesis and degradation

    • DNA/RNA synthesis

• ATP levels continue to be adversely affected after reperfusion due to mitochondrial injury, as demonstrated by a decrease in mitochondrial mass and activity.

  • Depending on the original insult, these effects on the mitochondria can persist late into reperfusion.

  • Mitochondria are also a major contributor to oxidative injury occurring during I/R.

• Sterile inflammation is another characteristic feature of I/R injury, and this is primarily attributed to actions of the innate immune system.

  • Neutrophil-mediated oxidative injury is the most prominent deleterious process during the inflammatory phase of hepatic I/R injury.

  • Damage-associated molecular patterns (DAMPs) are released by injured hepatocytes after I/R.

    • Examples of DAMPs include mitochondrial DNA, high-mobility protein group B1 (HMGB1), and cold-inducible RNA-binding protein (CIRP).

  • DAMPs are recognized by pattern recognition receptors (PRRs) on innate immune cells.

    • Examples of PRRs include toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors (NLRs), and retinoic acid–inducible gene I-like receptors (RLRs).

    • TLR 4 is a PRR that has been shown to contribute to the pathogenesis of hepatic I/R injury.

  • In addition to the effects of the innate immune response, there is growing evidence to support a proinflammatory adaptive immune response in I/R injury, with CD4 T cells playing a key role.⁴

• Several protective mechanisms are also activated during I/R.

  • The activation of the autophagy salvage pathway has been demonstrated after I/R injury.

    • Autophagy targets dysfunctional organelles and large macromolecules for lysosomal degradation.

    • It does this while also generating energy, thereby possibly diminishing the existent energy deficit.

  • The inflammatory response has also been implicated in the regenerative process necessary for healing after I/R.

CLINICAL TRIALS

• Perhaps the most studied clinical intervention postulated to have a beneficial impact on ischemic injury is ischemic preconditioning (IP).

  • IP involves clamping the vascular supply to an organ for short periods prior to an anticipated ischemic event.

  • The use of IP has been limited in transplantation due to the associated ...